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Genetic Dissection of LRRK2 Domains Critical For Pathogenesis via BAC Transgenic Approach

Mutations in the LRRK2 gene are responsible for certain types of familial Parkinson’s disease. The protein product of the LRRK2 gene has a complex structure and to date, research has focused on a possible abnormal increase in one of its enzymatic actions as the underlying link to PD, but other enzymatic features of the protein may also contribute. In this study, we will address specifically whether different enzymatic activities are required for PD-like pathogenesis using mice genetically engineered to express different forms of the LRRK2 gene.
Project Description: 
To better understand the pathogenesis, we have genetically engineered mice that carry the LRRK2 gene with disease-causing mutations and exhibit many of the features of PD pathology. In this study, we will make two additional pre-clinical models which express altered forms of the LRRK2 gene that do not have enzymatic activity. We will examine whether loss of this activity suppresses or enhances PD-like pathology in the mice, to address specifically whether such activity is required.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This knowledge is not only important for understanding disease mechanisms, but also for strategizing therapeutic development: Depending on which enzymatic function of LRRK2 is required for disease-like pathology, drug screening efforts should be focused on finding LRRK2 specific modifiers of that activity.
Anticipated Outcome: 
Two main outcomes are expected:
1.We will generate genetically engineered mice that carry the PD-related mutated LRRK2 gene but that lack enzymatic activity. These mice are valuable tools for future studies in this field.
2. We will answer the question as to whether LRRK2 enzyme activity, as well as which specific activity, is required for PD-like pathology.


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